Staphylococcus aureus causes millions of infections in the US annually, and each year, at least 72,000 cases of severe invasive disease and 10,000 deaths are attributed to the difficult-to-treat methicillin-resistant S. aureus (MRSA). In the US, a community-associated (CA) MRSA clone, USA300, is known to be a particularly common, hypervirulent strain type that spreads easily and persists for a prolonged period in households. Historically, Native Americans and indigenous people in general have been burdened by high rates of infectious disease. There is data to suggest the rate of S. aureus invasive disease among Native Americans may be double that of the general population; however, few studies of S. aureus have been conducted among these populations and surveillance data, which are integral for control efforts, remain limited. Consequently, little is known about the burden of invasive disease, asymptomatic carriage rates, antibiotic resistance prevalence, and transmission dynamics in these communities. Identifying disparities in these rates and elucidating routes of transmission have direct implications for control efforts in clinical and community settings among indigenous people and epidemiologically similar communities abroad. Further, fundamental questions regarding S. aureus evolution and pathology remain unanswered. These include the evolution of traits responsible for persistent carriage and transition from carriage to disease as well as the relative contribution of host risk factors, pathogen genomics, and pathogen-pathogen interactions to this dynamic. In this study, we seek to determine the comparative importance of host and pathogen factors associated with disproportionate rates of disease among Native Americans by combining host risk factor analysis, pathogen whole-genome sequencing, pathogen phylodynamic analysis, and comparative genomics. To this end, we will investigate genomic epidemiology of S. aureus among Native Americans living on or around Navajo Nation or White Mountain Apache (N/WMA) tribal lands, identifying invasive disease among individuals seeking care at Indian Health Service hospitals (Aim 1), assessing carriage in the community (Aim 2), and investigating host and pathogen factors associated with carriage, disease, and transmission (Aim 3). Expanding on Aim 3, we will investigate the population structure and origins of the N/WMA SA strains using phylogenetics to determine if they are representative of prevalent US lineages, including the dominant CA-MRSA USA300. We expect that the study population will have a higher S. aureus carriage prevalence than the general US population as well as a greater proportion of strains that are methicillin resistant compared to national trends. We also anticipate that transmission is driven, in part, by population- specific, community-associated risk factors, and involves strains genetically related to USA300. Understanding the genomic epidemiology of S. aureus provides tools to control it. Reduction of disease rates depends on preventing transmission, and our determination of risk factors will identify high-risk populations that can be targeted for preventive interventions. Further, we will address larger evolutionary questions regarding the emergence and spread of S. aureus lineages and the adaptive evolution of clinically relevant traits. Our long-term goal is to understand the underlying factors precipitating a disproportionate burden of disease and the interaction between SA and other respiratory bacteria.